Novel Synthetic Inhibitors of Selectin-Mediated Cell Adhesion: Synthesis of 1,6-Bis[3-(3-carboxymethylphenyl)-4-(2-α-d-mannopyranosyloxy)phenyl]hexane (TBC1269)
- 28 February 1998
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 41 (7) , 1099-1111
- https://doi.org/10.1021/jm9704917
Abstract
Reports of a high-affinity ligand for E-selectin, sialyl di-Lewisx (sLexLex, 1), motivated us to incorporate modifications to previously reported biphenyl-based inhibitors that would provide additional interactions with the protein. These compounds were assayed for the ability to inhibit the binding of sialyl Lewisx (sLex, 2) bearing HL-60 cells to E-, P-, and L-selectin fusion proteins. We report that dimeric or trimeric compounds containing multiple components of simple nonoligosaccharide selectin antagonists inhibit sLex-dependent binding with significantly enhanced potency over the monomeric compound. The enhanced potency is consistent with additional binding interactions within a single selectin lectin domain; however, multivalent interaction with multiple lectin domains as a possible alternative cannot be ruled out. Compound 15e (TBC1269) showed optimal in vitro activity from this class of antagonists and is currently under development for use in the treatment of asthma.Keywords
This publication has 26 references indexed in Scilit:
- Sialosyl-Fucosyl Poly-LacNAc without the Sialosyl-LexEpitope as the Physiological Myeloid Cell Ligand in E-Selectin-Dependent Adhesion: Studies under Static and Dynamic Flow Conditions,Biochemistry, 1997
- Discovering High-Affinity Ligands for Proteins: SAR by NMRScience, 1996
- The Synthesis of Novel 6‐Amido‐6‐Deoxy‐L‐Galactose Derivatives as Potent Sialyl Lewisx MimeticsAngewandte Chemie International Edition in English, 1996
- Glycomimetic selectin inhibitors: (α-D-mannopyranosyloxy)methylbiphenylsBioorganic & Medicinal Chemistry Letters, 1996
- Sialyl Lewis x Liposomes as a Multivalent Ligand and Inhibitor of E-Selectin Mediated Cellular AdhesionJournal of the American Chemical Society, 1996
- Structure-Activity Relationships of Sialyl Lewis x-Containing Oligosaccharides. 1. Effect of Modifications of the Fucose MoietyJournal of Medicinal Chemistry, 1994
- Multivalent sialyl-LeX: potent inhibitors of E-selectin-mediated cell adhesion; reagent for staining activated endothelial cellsGlycobiology, 1994
- Selectins.Journal of Clinical Investigation, 1993
- Recognition by Elam-1 of the Sialyl-Le x Determinant on Myeloid and Tumor CellsScience, 1990
- Lectins as Cell Recognition MoleculesScience, 1989